Long-term renal survival in HIV-associated nephropathy with angiotensin-converting enzyme inhibition

BACKGROUND: Human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) is the most common cause of end-stage renal disease (ESRD) in HIV-infected patients. Angiotensin-converting enzyme (ACE) inhibition has previously shown a short-term benefit in HIVAN. This study examines the long-term effects of ACE inhibition on renal survival in HIVAN. METHODS: In this single-center prospective cohort study, 44 patients with biopsy-proven HIVAN were enrolled prior to the onset of severe renal insufficiency (serum creatinine or=two antiviral drugs for >or=30 consecutive days, CD4 lymphocyte count, initial median serum creatinine concentration, or proteinuria. Risk of renal failure was reduced with ACE inhibitors (RR = 0.003, P < 0.0001). Exposure to antiretroviral therapy did not have a significant impact on the risk of renal failure. Of the ACE inhibitor-treated group, 87.5% survived compared with 21.4% of the control group (P < 0.001). CONCLUSION: ACE inhibition initiated prior to severe renal insufficiency may offer long-term renal survival benefits in HIVAN. Diagnosis should be sought early in patients with clinical signs suggestive of HIVAN.     

Spontaneous renal CT-scan hyperdensity of an HIV-associated nephropathy

Case A 27-year-old African woman was hospitalized because of a nephroticsyndrome associated with renal failure (creatinine clearance:56 ml/min). She had been given a diagnosis of     

Quantitation of viral DNA in renal allograft tissue from patients with BK virus nephropathy

BACKGROUND: BK virus (BKV) allograft nephropathy (BKVAN) is a complication in renal transplantation recipients. Histopathology is the gold standard for diagnosis. Quantitative polymerase chain reaction (PCR) assay for renal biopsy has not been evaluated as a diagnostic test. Determination of renal BKV load may identify patients at risk for disease before histologic nephropathy. METHODS: Quantitative PCR assay for BKV DNA was performed in 28 biopsies of patients with BKVAN; 50 biopsies were performed before a diagnosis of BKVAN, and 126 control biopsies were from patients without a history of BKVAN. RESULTS: BKV DNA was present in 19 of 50 (38%) biopsies performed 1 to 164 weeks before diagnosis of BKVAN. The viral load (mean 216 copies/cell) was lower than in biopsies of patients with BKVAN (mean 6063 viral copies/cell, <0.05). In 10 of 127 (7.8%) control biopsies, a low level of BKV DNA (mean 3.8 copies/cell) was found in three biopsies from chronic allograft nephropathy patients; two biopsies with acute rejection; four biopsies with borderline change; and one biopsy with cytomegalovirus nephritis. CONCLUSION: BKV load exceeding 59 copies per cell identified all cases of BKVAN. The diagnostic sensitivity, specificity, positive predictive value, and negative predictive value of quantitative PCR were 100%, 92.1%, 73.6%, and 100%, respectively. Lower levels of BKV DNA were identified in biopsies performed before viral nephropathy development. Future research will determine if earlier recognition of at-risk patients allows application of antiviral strategies to improve graft outcome.     

HIV-associated nephropathy and end-stage renal disease in children in the United States

Single-center studies have reported that HIV-associated nephropathy (HIVAN) can occur in children and may have a clinical course and prognosis similar to that of adults. However, the prevalence and survival has not been reported for a national sample of children with HIVAN and end-stage renal disease (ESRD) on dialysis in the United States. We utilized the United States Renal Data System (USRDS) database to determine the prevalence, demographic information, and survival of children with HIVAN and ESRD in the United States. The Kaplan-Meier method was used to estimate survival of children with HIVAN and the log-rank test was used to compare their survival with children with focal segmental glomerulosclerosis (FSGS) and adults with HIVAN. Cox regression analysis was used to model adjusted hazard ratios (AHR) with HIVAN as a cause of ESRD and its impact on mortality during the study period, adjusted for potential confounders. Of the 7,732 patients identified with HIVAN, only 60 were younger than 21 years and were classified as children; 50% were males and the majority (88.3%) was black. The cumulative percentage survival of children with HIVAN at 12, 24, and 36 months was better than adults with HIVAN (76%, 62%, and 54% vs. 60%, 43%, and 34%). Survival of children with HIVAN who started dialysis after 1996 was significantly better than those who started dialysis in or before 1996 (log rank P value <0.043). However, the major factor associated with better survival on Cox proportional hazard analysis was female gender (male vs. female AHR 2.85, 95% confidence interval 1.04–6.73). We conclude that only a small number of children with HIVAN and ESRD have received dialysis in the United States. The prognosis of these children is better than that of adults with HIVAN and among children with HIVAN females have better survival than males.The data reported have been supplied by the United States Renal Data System (USRDS). The interpretation and reporting of these data are the responsibility of the author (s) and in no way should be seen as an official policy or interpretation of the United States government     

Treatment of HIV-associated nephropathy

HIV-Associated Nephropathy (HIVAN) is the most common cause of chronic renal disease in HIV-1 infected patients. The disease occurs predominantly in blacks between the ages of 20 and 64. In this population it is currently the third leading cause of end-stage renal disease. The majority of patients with HIVAN have an AIDS-defining condition when the kidney disease is diagnosed. Without treatment they progress to end-stage renal disease within weeks to months. Patients with HIVAN should be treated with highly active antiretroviral therapy (HAART). Treatment should prolong survival and may improve or stabilize kidney function. Steroids have short-term benefits but long-term benefits have not been shown. Converting enzyme inhibitors (CEI) seem to stabilize kidney function and appear to be most effective when administered early in the course of HIVAN. A randomized controlled trial comparing HAART therapy to HAART and CEI should be performed.     

Cytopathic effects of antigens in patients with IgA nephropathy

The cytopathic effects of extracts of pharyngeal cells from patients with IgA nephropathy on fibroblasts were determined. Autoradiographical analysis of antigens in the fibroblasts was also described. Freeze and thawed extracts of pharyngeal cells obtained from patients with IgA nephropathy, other glomerular diseases and healthy adults were cultured with fibroblasts such as Vero or Hel cells at 37 degrees C for 1 or 2 weeks. The cytopathic effects of fibroblasts were examined with a light microscope. In addition, the eluate obtained from renal tissues of IgA nephropathy was labeled with iodine-125 by the chloramine-T method. These cultured fibroblasts were incubated with iodine-125-labeled eluate from the same or other patients with IgA nephropathy. The degree of cytopathic effects of extracts of pharyngeal cells from patients with IgA nephropathy on Vero or Hel cells was significantly increased compared with that from patients with other glomerular diseases or healthy adults without glomerular diseases. The cytopathic effects of such fibroblasts were not inhibited by filtration of extracts of pharyngeal cells obtained from patients with IgA nephropathy. It was shown that the antibodies eluted from renal tissues of patients with IgA nephropathy specifically bound with the nuclear regions of such fibroblasts. It was suggested that some antigenic substances might exist in the epithelial cells of the upper respiratory tracts of some patients with IgA nephropathy, and that such antigens were able to be transferred to cultured fibroblasts.     

HIV-associated nephropathy in African Americans

Human immunodeficiency virus-1 (HIV-1) infection is associated with several glomerular syndromes, the most prevalent of which is HIV-associated focal segmental glomerulosclerosis (FSGS). At present, HIV-associated FSGS may account for up to 30% of patients in the United States entering end-stage renal disease (ESRD) as a consequence of FSGS. The mechanisms responsible for HIV-associated FSGS are not well defined, but evidence has been presented in favor of direct infection of renal parenchymal cells and toxicity of HIV-1 accessory proteins. HIV-associated FSGS has a striking predilection for patients of African descent. This likely has a genetic basis, although the gene or genes responsible have not yet been identified. One approach is to examine candidate genes for polymorphisms that are associated with disease. Another approach uses a genome-wide scan, relying upon linkage disequilibrium between DNA markers and the disease gene, to identify the causal gene or genes. African Americans are an admixed population, with genetic contributions from African, European, and Native American populations. In admixed populations, linkage disequilibrium between disease genes and marker genes can be exploited to identify disease genes, using an approach termed mapping by admixture linkage disequilibrium (MALD).     

肾脏局部血管紧张素受体表达与IgA肾病病理损伤的相关性

目的 观察应用ARB类药物对肾脏局部血管紧张素受体表达的影响,探讨血管紧张素受体表达与IgAN肾病(immunoglobulin A nephrology,IgAN)肾脏病理损伤的关系.方法 选取2013年1月至2014年12月在中日友好医院肾内科行肾穿刺活检,且病理诊断为IgAN的患者172例,采用Lee分级方法进行病理分级,应用免疫组化方法检测AT1、AT2和MAS受体在肾活检组织中的表达,观察应用ARB类药物对上述三种血管紧张素受体的影响,分析三种受体表达水平与Lee分级的相关性.结果 Lee分级Ⅲ级IgAN患者中,应用ARB大于30 d者肾脏血管的AT1受体表达较未应用者显著减少,肾小球的AT2受体表达量较未应用者显著增多.IgAN患者肾脏血管、肾小管间质上AT1受体的表达水平与Lee分级存在显著正相关.Ⅴ级IgAN患者肾小球上AT2受体的表达量较Ⅰ~Ⅳ级患者显著增多.结论 应用ARB类药物治疗可影响IgAN患者肾脏局部AT1、AT2受体表达,肾脏局部AT1、AT2受体表达与IgAN肾脏病理损伤程度存在一定相关性.     

HIV-1 induces renal epithelial dedifferentiation in a transgenic model of HIV-associated nephropathy

BACKGROUND: Human immunodeficiency virus-associated nephropathy (HIVAN) is the most common cause of renal failure in HIV-1-seropositive patients. Recent studies using an HIV-1 transgenic mouse model have demonstrated that expression of HIV-1 in the kidney is required for the development of HIVAN. What has remained unclear, however, is the renal cell type responsible for pathogenesis and the essential pathological process. METHODS: To address these issues, we used a transgenic murine model of HIVAN. We identified the cell types in kidney in which HIV transgene expression occurs using in situ hybridization. We evaluated evidence of proliferation by immunocytochemical analysis using an antibody to Ki-67 and cell type-specific markers, including WT-1, synaptopodin, Na+,K+-ATPase, adducin, and desmin. TUNEL assay was used to evaluate apoptosis. RESULTS: We found that glomerular and tubular epithelial cells express the HIV-1 transgene early in the disease process when renal architecture is well preserved. Transgene expression is lost, however, in tubular epithelial cells when they lose their differentiated cuboidal phenotype. In glomerular epithelial cells, dedifferentiation occurs with reduced expression of WT-1 and synaptopodin, in association with activation of desmin expression. Tubular microcysts also form with mislocalization of Na+,K+-ATPase expression to the lateral and apical cellular membranes. CONCLUSIONS: These studies support the hypothesis that the glomerular and renal epithelial cells are the primary targets of HIV-1 pathogenesis in the kidney. The essential pathologic process is dysregulation of the epithelial cell cycle with increased proliferation, apoptosis, cellular dedifferentiation, and altered cellular polarity.     

肾组织中乙型肝炎病毒抗原阳性和阴性IgA肾病的临床与病理对照

目的比较ＩｇＡ肾病（ＩｇＡＮ）肾组织中乙型肝炎病毒抗原（ＨＢＡｇ）阳性和阴性患者的临床与病理特点。方法收集经免疫组化检测证实的肾组织ＨＢＶ抗原阳性组２６例和阴性组５９例ＩｇＡＮ患者的临床和病理及随访资料。结果与阴性组相比，阳性组肾病综合征者多见，血红蛋白、血ＩｇＡ水平和肌酐清除率显著下降，免疫荧光以ＩｇＡ＋ＩｇＧ＋ＩｇＭ型者多见，肾组织病理损害以Ⅳ级为多，肾小球硬化、肾小管病变、间质炎症和纤维化程度均显著严重。两组在临床表现、实验室检查、病理改变及预后方面均有显著性差异，阳性组临床病理改变更严重、预后更差。结论两组是性质相差较大的病变，对阳性组进行抗病毒治疗尤为重要     

Significance of vascular endothelial growth factor expression in renal tissue of patients with preeclamptic nephropathy

OBJECTIVE: It was the aim of this study to evaluate the distribution and expression of vascular endothelial growth factor (VEGF) in kidneys of patients with preeclamptic nephropathy and their relationship with clinical and pathological manifestations. METHODS: From May 1993 to August 2004, 19 patients with a mean age of 28.1 +/- 4.53 years (range 23-40), diagnosed with preeclamptic nephropathy by renal biopsy, were enrolled in this study. Fifteen were nulliparous and 4 multipara. Their renal tissues were subjected to immunohistochemical staining by a four-layer peroxidase-antiperoxidase method using monoclonal anti-VEGF. Residual normal renal tissue obtained at nephrectomy served as control. The relationship between the expression pattern of VEGF and clinicopathological features was also investigated. RESULTS: The expression of VEGF markedly increased in renal tissues of patients with preeclamptic nephropathy at the early stage of gestation termination in comparison with normal controls. However, over time, it gradually decreased and reached the level of normal controls (100 vs. 71.43 vs. 20%, p < 0.05). The degree of endothelial proliferation in the glomeruli was closely related to the expression of VEGF, which was stronger in patients with diffuse endothelial proliferation than in those with segment proliferation (p < 0.05). In addition, there was a proportional relationship between the expression of VEGF and the level of urinary protein excretion (p < 0.05). CONCLUSION: The patients with preeclamptic nephropathy showed strong expressions of VEGF in glomeruli, which were closely associated with glomerular endothelial lesions and proteinuria, and over time, gradually weakened to normal level after gestation termination.     

Animal models of HIV-associated nephropathy

PURPOSE OF REVIEW: HIV-1-associated nephropathy is characterized clinically by proteinuria with azotemia and pathologically by collapsing focal segmental glomerulosclerosis with tubulointerstitial nephritis and microcystic tubular dilatation. This review summarizes the manner in which different transgenic animal models contribute to our knowledge of the pathogenesis of HIV-1-associated nephropathy. RECENT FINDINGS: The most widely studied has been a transgenic mouse model bearing a gag and pol-deleted proviral construct that develops renal disease with many of the clinical and pathologic characteristics seen in HIV-1-associated nephropathy. Studies using this model have helped to highlight the role of HIV-1 viral gene expression in renal cells, podocyte dysregulation, and genetic host factors in the pathogenesis of HIV-1-associated nephropathy. This model has provided the key insights that led to detection of HIV-1 in human kidney epithelial cells. Other transgenic models have helped define critical roles for individual HIV gene products (Nef and Vpr) in the pathogenesis of HIV-1-associated nephropathy. Transgenic mouse models have also provided a method to discover new treatments targeting various steps in the pathogenesis of this disease. SUMMARY: Transgenic animal models of HIV-1-associated nephropathy have contributed greatly to the progress made toward understanding the pathogenesis of this disease.     

Preparation of specific antisera against antigens from pharyngeal cells in patients with IgA nephropathy

Rabbit antisera were produced against antigens obtained from pharyngeal cells of patients with IgA nephropathy (IgAN). Extracts of pharyngeal cells from patients with IgAN were frozen and thawed, and the supernatants were cocultured with fibroblasts (Vero and Hel cells). Pieces of renal biopsy specimens of the same patients were sectioned and centrifuged. The supernatants which contained IgA were incubated with the fibroblasts, and were stained with FITC-labeled anti human IgA antisera. Two positive (A and B) and one control Vero cell lines were destroyed and centrifuged. The precipitates were injected into rabbits, and rabbit antisera (A, B and control) were produced. Renal tissues from patients with IgAN and proliferative glomerulonephritis without IgA deposition (PGN) were stained with the FITC-labeled antisera. Positive stainings with FITC-labeled antiserum A was observed in 87% and that with FITC-labeled antiserum B in 55% of the patients with IgAN. No positive staining was detected with FITC-labeled control antiserum. There was also no positive staining with these antisera in renal tissues with PGN. The immunological specificity of the antisera was evaluated. It was found that these antisera did not react with complements components or immunoglobulins. The above findings suggested that some antigens from pharyngeal cells were deposited in the glomeruli from IgAN patients.     

IgA nephritis in HIV-positive patients: a new HIV-associated nephropathy?

Four HIV-positive patients were shown to have IgA-associated nephritis on biopsy, including one with anaphylactoid purpura. Three were homosexuals, while the fourth acquired the infection from his mother. All had hematuria, a variable degree of proteinuria and renal disease with a benign course. Serologic studies showed elevated levels of IgA as well as IgA immune complexes and rheumatoid factor. IgA antibodies to multiple HIV antigens were detected by Western blot. Pathologic studies showed tubuloreticular inclusions in endothelial cells and nuclear bodies in interstitial cells in all cases. HIV antigens were not detected in kidney biopsies by monoclonal antibodies nor was HIV viral genome demonstrated by in situ hybridization. The possibility that this represents a unique type of IgA-associated HIV nephropathy is discussed.